Bacteraemia is a constant threat to modern society and represents a significant burden to the healthcare system. In Australia alone it is estimated that there are 200,000 episodes of hospital-acquired infections each year, accounting for up to 2 million bed days in hospital. Patients who develop infections remain in hospital three times longer than other patients, resulting in additional costs and a lack of available beds for alternative uses. A significant number of these patients (estimated at 12,000 per year in healthcare) go onto develop blood stream infections. Of these 17-29% will die whilst in hospital, primarily due to ineffective treatment options. Staphylococcus aureus is the most important of these pathogens with a 20% mortality rate by 30 days. The ability to become pathogenic on entering the blood stream results in life-threatening bone and joint infections, endocarditis, pneumonia and septicaemia. Although the public profile of serious staphylococcal infections is that they are hospital-acquired, it is important to recognise that 60% of serious S. aureus infections are now thought to begin in the community.
Conventional antibiotic treatment for S. aureus infections utilises penicillinase-resistant penicillin. However, resistance to this agent is now prevalent in Australian hospital-associated strains and community-associated strains. Multidrug resistant strains, such as the hospital strains of methicillin-resistant S. aureus (MRSA), are also now present in most Australian hospitals and vancomycin-intermediate S. Aureus (VISA) strains are starting to emerge. A survey of Australian hospitals in 2005-06 revealed 24% of all S. aureus isolates were MRSA. Strains not susceptible to vancomycin (considered the last line of defence) pose a particular clinical problem, because there are very few agents available to treat them, and those that do exist (such as linezolid) have notable toxicity. Furthermore, the efficacy of vancomycin against vancomycin susceptible strains of MRSA is thought to be suboptimal. All this equates to a patient with MRSA infection costing a hospital five times more than one with methicillin-sensitive S. aureus infection.
There is a need to replenish the drug-discovery pipeline with new antibiotics to combat drug-resistant bacteria, including Staphylococcus aureus, which are responsible for a huge and growing health care problem
Biotin Protein Ligase (BPL) is an essential enzyme found in all living organisms. BPL attaches the prosthetic group biotin (Vitamin H) onto a class of enzymes known as the biotin-dependent carboxylases. These enzymes play essential roles in metabolic reactions such as membrane biogenesis; a key process in all living organisms. As the attachment of a biotin prosthetic group is absolutely required for normal enzyme function, inhibition of BPL activity can be used to inhibit cell growth.
Given the essential role of BPLs in all organisms, inhibitors of the BPL enzyme from a pathogen would provide opportunities for either selective or broad-spectrum treatments for a range of non-viral infectious diseases.
Patent application WO 2009/062241 describes the crystal structure of the S. aureus biotin protein ligase and its use to identify molecules that interact with the biotin binding domain of the enzyme. WO 2006/056007 describes methods for the identification of BPL inhibitors.
However, neither of these documents discloses inhibitors of BPL.
It has now been surprisingly found that a certain class of compounds inhibit the essential metabolic enzyme BPL, and their structure is described in this patent application.
An object of the present invention is to provide a novel class of antibiotics.
A further object of the invention is to provide a novel class of antibiotic that are selective for a particular bacterial target.
Yet a further object of the present invention is to provide a novel class of antibiotic that are selectively imported into bacterial cells but not mammalian cells.
It is an object of the present invention to overcome, or at least substantially ameliorate, the disadvantages and shortcomings of the prior art.
Other objects and advantages of the present invention will become apparent from the following description, taking in connection with the accompanying drawings, wherein, by way of illustration and example, an embodiment of the present invention is disclosed.